Rheumatoid Arthritis (RA) is an autoimmune disease that affects joints and extra-articular sites, leading to joint destruction, significant morbidity and increased mortality. Analysis of another autoimmune disease, Type 1 Diabetes Mellitus (DM), has shown that the majority of individuals ultimately affected with that particular disease exhibit 3 phases of disease progression: 1) Carriage of genetic risk primarily through HLA associations, 2) Presence of clinically silent autoantibodies for at least several years, and 3) Clinically apparent hyperglycemia. We propose that RA also exhibits these phases of disease and that, in a similar manner as Type 1 DM, analysis of epidemiologic associations within the genetically at-risk, autoantibody positive but clinically asymptomatic population of unaffected individuals will provide important insights into the pathogenesis of this disease. Previous analyses of individuals affected with RA has established a significant relationship of the "shared epitope" that is carried within certain HLA DR4 and DR1 alleles to both the genetic risk and severity of RA. There is also a newly-established relationship between the presence of RA in affected individuals and highly specific RA-related autoantibodies designated anti-cyclic citrullinated peptide (CCP) antibodies. Several studies have also demonstrated that anti-CCP and other RA-related autoantibodies may be present several years prior to the onset of clinical disease. However, with the exception of preliminary data we have recently developed, little is known about the association of high-risk HLA alleles and the presence of RA-related antibodies in any population that is genetically at-risk but not yet affected by RA. In addition, associations between exposures such as smoking, coffee, estrogens, pregnancy, infections, and environmental toxins such as silica and the presence of RA-related autoantibodies are also poorly understood. From previous population studies we know that first degree relatives (FDRs) of individuals affected with RA exhibit a substantially increased risk of developing disease, likely due to both genetic and environmental factors. We propose to identify and study a population of FDRs of individuals with RA in order to address the following specific aims: Specific Aim #1: In unaffected FDRs of individuals with RA, determine the association between the carriage of high risk HLA alleles and the presence of RA-related autoantibodies. Specific Aim #2: In this population of unaffected FDRs, determine the association between epidemiologic exposures and the presence of RA-related autoantibodies. We believe that defining the relationship between these factors is important to increasing the understanding of the immunopathogenesis of RA as well as potentially developing strategies for the selection of clinically unaffected individuals who would be candidates for prevention modalities or very early therapeutic interventions.